Allogenic donor splenocytes pretreated with antisense peptide against B7 prolong cardiac allograft survival

Abstract

SUMMARYThe interaction of T cell CD28/CTLA-4 receptors with B7 on antigen-presenting cells (APCs) represents an important co-stimulatory pathway in T cell activation or anergy. Our previous study indicated that recipients immunized with allogenic donor immature dendritic cells (DCs) or resting B cells could induce specific immune tolerance and prolong allograft survival. A possible mechanism for this observation is that the expression of B7 molecules is either at a low level or lacking on these cells. The present study investigates whether blockade of B7 molecules on donor splenocytes with a B7 antisense peptide (B7AP), i.e. a peptide analogue of the CD28-binding region, could induce specific immune tolerance and prolong allograft survival in the recipients. Both the lymphocyte proliferation reaction and the mice pinna cardiac allograft experiment were performed to evaluate the role of B7AP in inducing specific immune tolerance in recipients in vitro and in vivo . The results showed that 56·65% and 20·52% of C57BL/6 splenocytes expressed B7.1 and B7.2 molecules, respectively, on their cell surface. There were no significant changes of the B7 expression on such splenocytes after being treated by the B7AP (53·28% and 19·06%, respectively). B7AP inhibited the mixed lymphocyte reaction by up to 38·4% and a dose-response correlation was observed for inhibition. The recipients (BALB/c) immunized with B7AP-pretreated C57BL/6 splenocytes induced a specific immune hypo-response (43% versus control) and notably prolonged survival of the C57BL/6 cardiac allograft by up to 20·3 days. In contrast to the normal saline group (average: 8·6 days) and FTD 10 control peptide group ( < 4 days), the cardiac allograft survival of the test group was extended for an additional 11·7 days. These results strongly support the notion that immunization with donor splenocytes, which had been pretreated with B7AP, induced specific immune tolerance and prolonged allograft survival in the recipients.

Co-Delivery of Autoantigen and B7 Pathway Modulators Suppresses Experimental Autoimmune Encephalomyelitis

“…In order to investigate the application of SAgAs targeting the B7 pathway, we selected three peptides (B7AP, CD80-CAP, sF2), which had been previously reported to bind B7 (Table I). Two peptides used in this study, B7AP and CD80-CAP, have been shown to inhibit inflammatory immune response in several rodent autoimmune models (18)(19)(20)30,37). In contrast, the peptide mimic of CTLA-4 (sF2) was originally selected for this study as a positive control to enhance the immune response by blocking the B7:CTLA-4 regulatory interactions (31).…”

“…Peptides selected for use in this study were previously shown to interact with and modulate the B7 signaling pathway (Table I) (18)(19)(20)30,31). SAgAs targeting the B7 pathway were created by co-grafting to hyaluronic acid polymers (HA) both autoantigen (PLP 139-151 ) and B7-binding peptides (B7AP, CD80-CAP, or sF2) as previously reported (15,24,25).…”

“…Methods employing peptides targeting different aspects of the B7 signaling pathway have been tested in animal models of RA, MS, and allograft rejection with positive results (18)(19)(20)(21). These peptide therapies are thought to work by blocking delivery of the co-stimulatory signal from the pAPC, resulting in T cell anergy and promotion of tolerance to treat autoimmunity (14).…”

The complex role of B7 molecules in tumor immunology

“…Engagement of B7-1 or B7-2 on APCs with CD28 on T cells provides costimulatory signals that are required for the activation of naïve T cells, and T-cell responses are severely inhibited in Cd28 -knockout (KO) mice [5,6]. The interaction of CTLA-4 with the same ligands acts as a negative regulator of CD28-dependent T-cell activation [7,8], and loss of CTLA-4 leads to severe lymphoproliferation and fatal multiorgan destruction via autoimmunity [9]. In this way, the B7-1/B7-2–CD28/CTLA-4 pathway represents either a costimulatory or coinhibitory pathway in modulating the T-cell response.…”

Immune modulating peptides for the treatment and suppression of multiple sclerosis

“…Peptides derived from the conserved region of CD28 containing the motif MYPPPY bind to B7 and have suppressed EAE in B10.PL mice [136]. A similar but shorter peptide that showed efficacy in prolonging cardiac allograft rejection [137] was tested in our laboratory, and results indicated significant suppression of PLP 139-151 -induced EAE in SJL/J mice (unpublished data).…”